Niflumic acid-induced increase in potassium currents in frog motor nerve terminals: effects on transmitter release

The actions of the nonsteroidal antiinflammatory drug niflumic acid were studied on frog neuromuscular preparations by conventional electrophysiological techniques. Niflumic acid reduced the amplitude and increased the latency of endplate potentials in a concentration-dependent manner. Neuromuscular junctions pretreated with niflumic acid (0.05–0.5 mM) showed much less depression than control when they were stimulated with trains of impulses. Inhibition of acetylcholine release was reverted by raising the extracellular Ca²⁺ concentration but not by simply washing out the preparations with niflumic acid-free solutions. Pretreatment with indomethacin (0.1 mM), another nonsteroidal antiinflamatory drug, did not affect the niflumic acid-induced inhibition of evoked responses. Niflumic acid (0.1 mM) did not change the amplitude of miniature endplate potentials and had a dual action on the frequency of miniatures: it decreased their frequency at 0.1 mM whereas it produced an enormous increase in the rate of spontaneous discharge at 0.5 mM. Niflumic acid (0.1–1 mM) reversibly increased the amplitude and affected the kinetics of presynaptic voltage-activated K⁺ current and Ca²⁺-activated K⁺ current in a concentration-dependent manner. Niflumic acid (0.1–1 mM) irreversibly decreased the amplitude and reversibly affected the kinetics of the nodal Na⁺ current. Indomethacin (0.1 mM) had no effect on presynaptic currents. In conclusion, niflumic acid reduces acetylcholine release by increasing presynaptic K⁺ currents. This may shorten the depolarizing phase of the presynaptic action potential and may reduce the entry of Ca²⁺ with each impulse.     

Further evidence for the dynamic formation of transmitter quanta at the neuromuscular junction.

Fatt and Katz (Nature 166:597-598, 1950; J Physiol 117:109-128, 1952) attributed miniature endplate potentials (MEPPs) to the action of a standard quantity of transmitter, the quantum (Del Castillo and Katz, J Physiol 124:560-573, 1954). Quantal packets of transmitter were proposed to be preformed (Del Castillo and Katz, In CNRS Paris (Ed): "Microphysiologie comparée des éléments excitables" 67:245-258, 1957) and stored in large numbers in the motor nerve terminal. Statistical analyses of intervals between MEPPs and numbers of quanta composing small endplate potentials indicated that quantal release was a random process and that release sites functioned independently of each other. With the discovery of synaptic vesicles it was proposed that each contained one quantum of transmitter. The quantal-vesicular hypothesis (Del Castillo and Katz, as cited above) fails, however, to explain amplitude distributions of MEPPs that are skewed and/or that show multiple peaks (Kriebel et al., Brain Res Review 15:167-178, 1990). The drop formation process (Shaw, "The Dripping Faucet as a Model Chaotic System," Santa Cruz, CA: Aerial Press, Inc., 1984) was shown to generate amplitude classes of drops that were similar to classes of MEPPs which suggested that rapid changes in quantal size and ratios of skew- to bell-MEPPs could be explained with a simple dynamic process which determines quantal size at the moment of release (Kriebel et al., as cited above, 1990). Further similarities between miniature endplate currents (MEPCs) and the formation of drops are reported here. We found that rapid changes in MEPC amplitudes and time courses, which accompany an increase in frequency, mimic changes in drop sizes that accompany increases in flow rate. MEPC intervals have a minimum and their distributions are comparable to those of drop intervals. During an increased rate of transmitter release, MEPP amplitudes and intervals were positively correlated. The results suggest that spontaneously released transmitter "packets" are formed at the moment of release and that transmitter supply to the process that forms packets is continuous.     

Transient GABA immunoreactivity in cranial nerves of the chick embryo

The distribution and time course of gamma-aminobutyric acid (GABA) immunoreactivity was investigated in the cranium of the chick embryo from 2 to 16 days of incubation (E2-16). A fraction of nerve fibers transiently stains GABA-positive in all cranial motor nerves and in the vestibular nerve. Cranial motor nerves stain GABA-positive from E4 to E11, including neuromuscular junctions at E8-11; labeled fibers are most frequent in the motor trigeminal root (E6-9.5). Substantial GABA staining is present from E4 to E10 in a subpopulation (1-2%) of vestibular ganglion cells. Their peripheral processes are labeled in the vestibular endorgan, predominantly in the posterior crista. Some GABA-positive fibers are present in the olfactory nerve (after E5) and in the optic nerve (after E9.5); their immunoreactivity persists throughout the period investigated. Transient GABA immunoreactivity follows "pioneer" fiber outgrowth and coincides with the formation of early synaptic contacts. GABA-containing neurons may change their neuronal phenotype (loss of GABA expression) or they may be eliminated by embryological cell death. Periods of cell death were determined in cranial ganglia and motor nuclei by aggregations of pycnotic cells in the same embryonic material. The periods of embryonic cell death partly coincide with transient GABA immunoreactivity. The function(s) of transient GABA expression is unknown. Some lines of evidence suggest that GABA has neurotrophic functions in developing cranial nerves or their target tissue. In the developing neuromuscular junction, GABA may be involved in the regulation of acetylcholine receptors.     

Comparison of β-adrenoceptors mediating vasodilatation in canine subcutaneous adipose tissue and skeletal muscle

Blood flow changes in response to various drugs in simultaneously autoperfused canine subcutaneous adipose tissue and gracilis muscle were compared to study the vascular β-adrenoceptors. Compared to isoprenaline the β₂-selective agonist salbutamol was 4–6 times more potent as a vasodilator in the muscle than in adipose tissue. Furthermore two β₁-selective agonists (Tazolol and H80/62) caused vasodilatation in adipose tissue but not in the gracilis muscle. When given by close i.a. injection after β-adrenoceptor blockade, adrenaline was a more potent vasoconstrictor than noradrenaline in both tissues. Before β-blockade, however, noradrenaline was the more potent vasoconstrictor in the gracilis muscle whereas adrenaline was more potent in adipose tissue. Intravenous infusion of adrenaline in doses causing vasodilatation in the muscle caused vasoconstriction in adipose tissue whereas intravenous infusion of noradrenaline caused vasoconstriction in both tissues. The present findings suggest that the β-adrenoceptors mediating vasodilatation in skeletal muscle are mainly of the β₂-type, whereas β₁-adrenoceptors seem to predominate in subcutaneous adipose tissue. Since adrenaline is a much more potent β₂- than β₁-agonist, these differences point to different roles of intravascular adrenaline in the two sites. In skeletal muscle circulating adrenaline is mainly a vasodilator whereas in subcutaneous adipose tissue it mainly acts as a vasoconstrictor.     

Effects of the novel dopamine DA2-receptor agonist carmoxirole (EMD 45609) on noradrenergic and purinergic neurotransmission in rat isolated kidney

Summary The effects of the classical dopamine DA₂-receptor agonist quinpirole (LY 171555) and the recently characterized DA₂-receptor agonist, carmoxirole (EMD 45609), on neurotransmission in rat isolated kidney were investigated. After preincubation with ³H-noradrenaline, the renal nerves were electrically stimulated. The stimulation induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. Quinpirole (0.3 mol/l) inhibited S-I outflow of radioactivity and pressor responses to renal nerve stimulation (RNS) at 1 Hz. Both effects of quinpirole were blocked by the DA₂-receptor antagonist S(–)-sulpiride (10 mol/l). The ₁, ₂-adrenoceptor antagonist phentolamine (1 mol/l) did not block the inhibitory effect of quinpirole. Carmoxirole (0.003 and 0.03 mol/l) did not alter and carmoxirole (0.3 mol/l) even enhanced S-I outflow of radioactivity, however, pressor responses to RNS were markedly reduced by carmoxirole (0.003–0.3 mol/l). Pressor responses to RNS were also markedly reduced by the ₁-adrenoceptor antagonist prazosin (0.1 mol/l). Carmoxirole (0.3 mol/l), prazosin (0.1 mol/l) and phentolamine (1 mol/l) totally abolished pressor responses to exogenous noradrenaline (0.05 mol/l). In contrast, quinpirole (0.3 mol/l) did not alter pressor responses to exogenous noradrenaline (0.05 mol/l). Furthermore, carmoxirole (0.003–0.3 mol/l) markedly reduced pressor responses induced by the ₁-adrenoceptor agonist methoxamine (1 mol/l) but even the highest concentration of carmoxirole (0.3 mol/l) had no effect on pressor responses induced by bolus injections of either neuropeptide Y (1.5 ng) or angiotensin II (1 ng). Phentolamine (1 mol/l) by itself markedly enhanced S-1 outflow of radioactivity and pressor responses to RNS were virtually unchanged. In the presence of phentolamine carmoxirole (0.03 and 0.3 mol/l) and quinpirole inhibited S-I outflow of radioactivity and pressor responses to RNS. Phentolamine resistant pressor responses to RNS were also inhibited by the P_2X-receptor desensitizing agent , -methylene adenosine triphosphate (mATP, 1 mol/l), which by itself in the presence of phentolamine did not alter S-I outflow of radioactivity. The inhibitory effects of carmoxirole (0.3 mol/l) in the presence of phentolame (1mol/l) were antagonized by S(–)-sulpiride (10 mol/l). The data suggest that activation of prejunctional DA₂-receptors by quinpirole inhibits noradrenaline release and thereby reduces pressor response to RNS at 1 Hz in rat isolated kidney. Carmoxirole activates prejunctional inhibitory DA₂-receptors, but this effect is masked by simultaneous blockade of inhibitory prejunctional -adrenoceptors. Pressor responses to RNS at 1 Hz in rat isolated kidney are largely due to neuronally released noradrenaline whereas phentolamine resistant pressor responses to RNS at 1 Hz are most likely due to ATP, which is co-released with noradrenaline. Carmoxirole inhibits pressor responses to RNS at 1 Hz as well as pressor responses induced by either exogenous noradrenaline or methoxamine by blocking postjunctional ₁-adrenoceptors. In addition carmoxirole and quinpirole seem to block phentolamine resistant pressor responses by inhibiting ATP release through activation of prejunctional DA₂-receptors. Send offprint requests to L. C. Rump at the above address     

冠心病介入治疗后血浆中新型气体信号分子硫化氢水平的变化及机制研究

目的观察冠心病行经皮冠状动脉介入(PCI)治疗后患者血浆中新型气体硫化氢的浓度变化,探讨其变化机制,从而揭示硫化氢(H2S)水平在冠心病发病及病程进展中的意义。方法随机选取2011年1月至2013年1月间心血管内科临床经冠脉造影确诊为冠心病的患者115例作为研究对象,同时选取48例冠脉造影正常者作为对照组。本研究中所有确诊为冠心病的患者均采取PCI治疗。所有研究对象于术前取股动脉血4 ml,冠心病患者行PCI治疗后即刻再取股动脉血4 ml,离心取血浆备用。分别采用敏感硫电极法和Griess法测定血浆中H2S和NO的含量。结果 1冠心病患者血浆H2S和NO的含量远远低于冠脉造影正常的对照组,差异有统计学意义(P0.01),行PCI治疗后与术前比较,血浆H2S和NO的含量明显升高,差异有统计学意义(P0.01),且与正常人相比差异无统计学意义(P0.05);2冠状动脉双支和多支病变的患者其血浆H2S和NO含量低于单支病变患者,差异有统计学意义(P0.05),经过PCI治疗后,各组血浆H2S和NO的含量明显升高,差异有统计学意义(P0.01)。结论血浆中H2S的含量与冠状动脉病变程度密切相关。行PCI治疗后,冠状动脉血液循环得以重建,血管内皮细胞功能得到恢复,随之NO水平得到恢复,从而提高血浆中H2S的水平。     

Therapeutic potential of new hydrogen sulfide-releasing hybrids

A new class of hydrogen sulfide (H₂S)-donating hybrids combined with pharmacologically active compounds is presented in this article. The pharmacological profiles of some hybrid lead compounds in the areas of inflammation, H₂S-donating diclofenac (ACS 15); cardiovascular, H₂S-donating aspirin (ACS 14); urology, H₂S-donating sildenafil (ACS 6); and neurodegenerative, H₂S-donating latanoprost (ACS 67) for glaucoma treatment and H₂S-donating levodopa (ACS 84) for Parkinson’s disease, are described. The new H₂S-releasing hybrids demonstrate remarkable improvement in activity and tolerability as compared with the related parent compounds, suggesting an active pharmacological role for H₂S. Finally the mechanism(s) of action of glutathione-dependent and independent, and of gas (H₂S) release (spontaneous or enzymatic) and its implications for clinical pharmacology perspectives will be also discussed.     

A combined application of lossless and lossy compression in ECG processing and transmission via GSM-based SMS

Abstract

This paper presents a software-based scheme for reliable and robust Electrocardiogram (ECG) data compression and its efficient transmission using Second Generation (2G) Global System for Mobile Communication (GSM) based Short Message Service (SMS). To achieve a firm lossless compression in high standard deviating QRS complex regions and an acceptable lossy compression in the rest of the signal, two different algorithms have been used. The combined compression module is such that it outputs only American Standard Code for Information Interchange (ASCII) characters and, hence, SMS service is found to be most suitable for transmitting the compressed signal. At the receiving end, the ECG signal is reconstructed using just the reverse algorithm. The module has been tested to all the 12 leads of different types of ECG signals (healthy and abnormal) collected from the PTB Diagnostic ECG Database. The compression algorithm achieves an average compression ratio of ～22.51, without any major alteration of clinical morphology.     

推拿联合经颅重复针刺法为主针刺治疗轻中度失眠的随机对照临床研究

目的:观察推拿联合经颅重复针刺法为主针刺治疗轻中度失眠的临床疗效。方法:将符合标准的60例轻中度失眠患者随机分为2组,即观察组30例、对照组30例。观察组给予推拿联合经颅重复针刺法为主针刺治疗。对照组给予艾司唑仑片口服治疗。2组疗程均为4周。记录并比较2组治疗前、治疗后日觉醒次数、日总睡眠时间;采用匹兹堡睡眠质量指数(PSQI)量表评价睡眠质量;采用抑郁自评量(SDS)与焦虑自评量表(SAS)评价焦虑、抑郁情绪;采用酶联免疫吸附法测定血清5-HT、NE水平。结果:治疗后,2组日觉醒次数、日总睡眠时间、睡眠质量、SAS评分、SDS评分较治疗前均显著改善,组内治疗前后比较差异具有统计学意义(P<0.01);观察组日觉醒次数、睡眠质量、SAS评分、SDS评分较对照组明显减少,组间比较差异具有统计学意义(P<0.01);观察组日总睡眠时间较对照组明显增加,2组比较差异具有统计学意义(P<0.01)。治疗后,2组血清5-HT、NE含量较治疗前均显著增加(P<0.01);观察组血清5-HT、NE含量较对照组明显增加,2组比较差异具有统计学意义(P<0.01)。结论:推拿联合经颅重复针刺法为主针刺治疗轻中度失眠临床疗效肯定,可以临床推广使用。